The genetic basis of cardiac disease in humans ranges from simple mutations to complex genetic traits. Until recently, genetics of canine and feline heart disease were poorly understood, with most studies examining inheritance patterns in line-bred individuals. In most cases, the complexity of the traits prevented authors from reaching firm conclusions regarding the mode of inheritance, let alone the specific genes involved.
Subsequent to the identification of genetic abnormalities in a number of cardiac diseases in humans, veterinary cardiologists and others began investigating analogous diseases in dogs and cats using a candidate gene approach. They failed to identify the affected gene(s) in the vast majority of these investigations, demonstrating the inherent problems of this approach.
With the advent of genome-wide association studies (GWAS), several gene candidates have been identified as potentially causal in canine and feline heart disease. This approach allows for rapid identification of regions of inhomogeneity between affected and non-affected individuals, and ignores lineage, or inheritance patterns. However, it does require accurate identification of the phenotype to properly segregate the populations.
Several inherited or familial cardiac diseases have now been shown to have a specific genetic basis in both dogs and cats. Most of these currently revolve around cardiomyopathies, with inheritance of congenital or developmental diseases being relatively uninvestigated at this time. However, with genomic studies growing ever-cheaper, in-roads into the genetic basis of many of the cardiac disease to which specific breeds are predisposed will be made over the coming years.
Canine Diseases With a Known or Highly Suspected Genetic Basis
Dilated cardiomyopathy (DCM) of Doberman Pinschers was the first canine cardiac disease to undergo genetic analysis. Candidate gene approaches, based on genetic mutations identified in humans with DCM failed to identify a gene associated with DCM in Doberman Pinschers. Recently, GWAS identified regions in affected Dobermans, which following more comprehensive analysis, revealed involvement of a mitochondrial gene associated with glucose metabolism (pyruvate dehydrogenase kinase 4, located on chromosome 14), previously unrecognized in DCM in humans. A second group recently identified a locus on chromosome 5 as potentially linked to Doberman DCM.
Similarly, GWAS of arrhythmogenic right ventricular cardiomyopathy (ARVC) in boxer dogs led to the discovery of abnormal striatin as a potential cause of ARVC. Mutations in this gene have not been identified in humans with ARVC. However, genes that interact with striatin have been shown to cause ARVC in humans.
Feline Diseases With a Known or Highly Suspected Genetic Basis
Hypertrophic cardiomyopathy (HCM) of Maine Coons was the first veterinary cardiac disease in which a genetic basis was identified. HCM remains the only feline disease in which a genetic basis has been established. Two different mutations in the same gene (myosin-binding protein C) have been described with HCM in Maine Coons and Ragdolls. Several studies have questioned the validity of these findings, reflecting the complexity of genetic expression in cats with the mutations.
Canine Diseases With Familial or Breed Predispositions
It is most probable that cardiac diseases that occur within specific breeds or lines within a breed have a genetic basis. In most cases, the genetic basis of these diseases is unknown. Limited linkage analysis has identified a likely genetic role for diseases such as subaortic stenosis (SAS) in Newfoundlands, tricuspid valve dysplasia in Labrador Retrievers, patent ductus arteriosus in poodles. However, in most cases, these diseases have been described as having a complex autosomal pattern of inheritance. Mitral valve disease in Cavalier King Charles Spaniels has also been shown to have a strong familial basis, with a complex inheritance pattern. Sudden cardiac death in German Shepherds has been extensively studied, but no genetic basis has been identified.
Diseases in which breed or familial predisposition has been identified (but without any analysis of inheritance) include pulmonic stenosis with aberrant coronary development in boxer dogs and Bulldogs, atrial septal defects in Standard Poodles, vascular ring anomalies in German Shepherds, SAS in Golden Retrievers, German Shepherds, Rottweilers and Boxers, DCM in Portuguese Water Dogs, sick sinus syndrome in Miniature Schnauzers and West-Highland White Terriers, and tetralogy of Fallot in Keeshonds. Multiple other breeds have been variously implicated as predisposed to certain congenital cardiac diseases, often with little solid evidence.
Feline Diseases With Familial or Breed Predispositions
Very few, if any, cardiac diseases, other than HCM, have been demonstrated to have a familial or breed predisposition in cats.
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